Abstract For a broad range of taxonomically diverse organisms, nutrient availability acts as a powerful modulator of health and longevity through molecular mechanisms that are largely unknown. In mammals, longevity through diet restriction is accompanied by a broad-spectrum improvement in health during aging. We and others have used genetic and environmental manipulations in invertebrate model systems to establish that nutrient- mediated longevity is a regulated response that activates specific neurons and that involves neuroendocrine systems targeting conserved pathways in peripheral tissues. These target pathways have since been manipulated in mammalian systems to improve longevity or other health-related phenotypes, which reinforces the effectiveness of simple model systems for aging research. Nevertheless, the development of successful human interventions requires a much better mechanistic understanding of how neuronal inputs are integrated and how critical metabolic processes implement the changes that underlie the effects of diet-restriction. In this renewal, we build upon the results from the parent award to continue our dissection of the molecular mechanisms of DR. First, neuronal control of the DR response will be examined by elucidating the mechanisms through which a newly described gene that we call ponchik modulates obesity, feeding behavior, and longevity. We will also take advantage of a completed genetic screen to identify new modulators of dietary restriction that act exclusively in the fly brain. Second, we have discovered that the transsulfuration pathway (TSP), which controls the metabolism of sulfur-containing amino acids, actively promotes survival and metabolic homeostasis in response to nutritional and hormonal signals. We will test a model involving the TSP as an energy sensor that affects protein synthesis, xenobiotic and antioxidative responses, and the production of key signaling molecules that promote health and longevity, specifically under conditions of dietary restriction. The contributions of this project are two-fold. First, we will continue to elucidate the basic principles of how aging is controlled by the nervous system. Second, we will determine how the evolutionarily conserved process of transsulfuration promotes lifespan and influences energy balance. These contributions are significant because understanding the molecular details of how nutrient- and energy-sensitive neural circuits direct changes in peripheral tissues to alter lipid metabolism, behavior, and overall lifespan in a complex organism will illuminate basic principles of aging that can be applied to develop novel intervention strategies in human aging.